Cancer has become one of the most common complications of long-term HIV infection in the US, and may come to be an even greater threat in sub-Saharan Africa because of the delayed and incomplete access to antiretroviral therapy, the high prevalence of viral oncogens, and a larger number of years a person may be at risk for developing cancer due to pediatric HIV infection. In this region, the three AIDS-Defining Cancers, including Kaposi sarcoma (KS), non-Hodgkin Lymphoma (NHL), and invasive cervical cancer (ICC), remain among the most common cancers in the entire population. Over the past decade, the Fred Hutchinson Cancer Research Center has collaborated with the Uganda Cancer Institute to conduct collaborative research and training on infection-related cancers; and define the natural history, biology and treatment of HlV-associated malignancies (HIVAM). This work has revealed HIV-infected individuals with cancer are at significantly increased risk of death when compared with similar HIV-negative persons with cancer, and that the response to therapy varies dramatically within HIV-infected persons with the three ADCs. In the current proposal, we seek to understand the biologic basis for the differential natural history of ADCs in Uganda through the following Specific Aims: 1) To characterize the viral genetic diversity among two viral oncogens, human herpesvirus-8 (HHV-8) and human papillomavirus (HPV), and begin to explore the relationship between genetic variants and the natural history of KS and ICC, respectively; 2) To describe the evolution of the cellular immune response among persons with AlDS-defining malignancies who initiate antiretroviral therapy and chemotherapy; 3) To expand the capacity to conduct state-of-the-art translational research in HIVAM in Uganda through optimizing scientific leadership among Ugandans who have been trained in HIVAM research, maintaining a unique and extraordinary biorepository for the study of HIVAM in Uganda, expanding the enrollment of patients with ADCs into translational studies of the natural history of their malignancies, and providing the administrative support for collaborative biomedical research across two continents.